LU85841A1 - STEREOSPECIFIC PROCESS FOR THE PREPARATION OF AN ACETOXYAZETIDINONE - Google Patents

Description

DESCRIPTIVE MEMORY

’FILED IN SUPPORT OF A REQUEST

OF

PATENT

FORMED BY

BRISTOL-MYERS COMPANY.

t for

Stereospecific process for the preparation of an acetoxyazetidinone.

1. Field of the invention.

The present invention relates to a new stereospecific process for preparing a key intermediate used for the synthesis of carbapenems and antibiotic penemes.

CD.YCM.3F - 1 - SY-1757 2. Known state of the art.

The present invention relates to a new * stereospecific process for converting 6-aminopenicillanic acid into an optically active intermediate azetidinone of formula s Λ OR "0

I H H II

L ^ occh,

NH

O

where R "represents a conventional radical protecting the hydroxyl function and the absolute configuration at the carbon atoms 1 ′, 3 is 4 and R, R and R. The intermediates of formula I, which are known per se, t are key intermediates for the synthesis of antibiotic carbapênèmes and pétnèmes carrying an (R) -hydroxyethyl radical at position 6 of the carbapenem or penem nucleus and having the absolute R and S configuration at positions 5 and 6, respectively. genera, especially thienamycin produced by natural fermentation, are described in patents and scientific literature as having exceptional antibacterial activity.

Various methods of total synthesis for the preparation of the above antibiotic penemes and carbapenems have already been described, but so far they have not been satisfactory from the industrial point of view due to the large number of operations required and the need to separate the mixtures of ·· "diastereoisomers thus obtained.

One approach to the synthesis of carbapenems - and penemes of the above type has been to start from CD.YCM.3F - 2 - SY-1757 6-aminopenicillanic acid (6-APA) which is an easy compound to obtain by fermentation. Hirai et al. in Hetero-- cycles 17; 201-207 (1982) describe a process for converting the optically active 4-acetoxy-3-azetidinone 6-APA of formula î Ä 1.0 "fii -I- Il J ·:, _ / 0CCH3

FT

A-NH

0 which can be converted, according to known techniques, into biologically active penemes and carbapenems. According to this process, 6-APA is converted to the azetidi-none above in accordance with the following diagram î f é CD.YCM.3F - 3 - SY-1757 in

X

U

CM

W * 'X ·

U M

cvj \ 8 / v i — 2

Y ~ {i t R

Y- * 3 "8 ^ ° a__L s” f 8 Yi!

'U

A W ^

î V * * L

I c XX

- N U U

♦> “\ V / δ 3- η ° Ή fi V“

\ _ 2 2 + Ö .......- V

1 Φ -H /% * M “gzX o ω o \ σ> x υ \ / Vv Σ υ o x / V m η o Z o X X vß N υ u i x CD.YCM.3F - 4 - SY-1757 t §

X

X

<g "<\ _o" \ ru I— 2

"Γ / —L

- CO— / V u CT - <* O <^ V-

t H

- CO— 'V

G —- H »O

you

X

O

O

υ ΓΟ

X

υ

X

CN

U

<

O

CP

X

CD.YCM.3F - 5 - SY-1757 ^ In particular # 6-AP A is esterified into the methyl ester and then converted according to ΐ known methods, for example those described in the published English patent ηβ 2,045,755A, into the methyl ester of 6,6-dibromopenicillin. This ester is then hydroxyethylated by the metal-halogen exchange process described in J. Org. Chem. 42: 2960-2965 (1977) into a mixture of the cis and trans diastereoisomers which, at least on a small scale, can be separated by chromatography for the release of the desired cis (R) -hydroxyethylated isomer. This isomer is silylated by means of t-butyldimethylchlorosiliane in the corresponding hydroxy-protected intermediate which is then subjected to reductive debromination by zinc to give a mixture of the cis and trans (R) -hydroxyethylated isomers of which the desired trans isomer can be isolated. The hydroxyethylated penicillin ester is then reacted c with mercuric acetate in acetic acid for the opening of the thiazolidine ring leading to an intermediate 4-acetoxyazetidinone, which is subjected to oxidation by potassium permanganate to 11 elimination of the β-methylerotonate entity and the formation of the desired optically active intermediate 4-acetoxyazetidinone.

An article by Tetrahedron Letters 23 (39): 4021-4024 (1982) describes the reaction scheme: CD.YCM.3F - 6 - SY-1757 <* · c in Œ ΙΟ

U

CM

x

U

CM

* O

U

Ή co y * t t _ΛΊ ο υ \ CO _ 0 in> -i O o a a: ® = "> Λ

U5 D U I

U * co C, <U ΠZU c

• H

CD

C + J

VQ> m œ Œ,} ° Φ> 1

m υ „, Ό 4D

U ^ 3 N F 0 Λ X U ^, U ™ 3 C m

nj S U I X

. O \ / yu Ό -H io yy y ~ (ês J-

w CO oCM

yz ^ Y-2 y_ / ° r ~ \ "^ V * cm o 'O m m Ä

2 ^ X

* lO

Φ U

wo> *; τ ^ 0 uo —— A: ° Γ 'CD.YCM.3F - 7 - SY-1757 ** In this case, the starting diazopenicillin ester is converted to 6,6-bis (phenylselenyl ) benzyl peni-ill cillinate which is hydroxyethylated by methylmagnesium bromide and acetaldehyde at -60 ° C into a mixture of diastereoisomers from which the desired cis • isomer can be isolated.

The optically active 4-acetoxyazetidinone can be used according to known methods for the synthesis of carbapenems and antibiotic penemes. For example, in Tetrahydron Letters 23 (22): 2293-2296 (1982), the conversion of this intermediate to thienamycin and in Chem is described. Pharm. Bull. ^ 9 (11): 3158-3172 (1981), the use of this intermediate for the synthesis of antibiotic penemes.

The methods described above are in principle useful for the large-scale synthesis of (8R) -hydroxyethylpenems and -carbapenems antibiotics, but lack stereospecificity at the aldolic condensation stage and at the reduction stage, it is that is to say that the hydroxyethylation of the dibromopenicillin or of the bis ester (phenylselenylJpenicillin and the reduction of these hydroxyethyl intermediates for the elimination of the bromo or phenylseleno radical lead to a mixture of diastereoisomers which must be separated to give the product Optically active sought, such separation, especially on an industrial scale, makes these processes much less efficient than they could otherwise be.

OVERVIEW OF THE INVENTION.

“'' '- I ni

The present invention relates to a new stereospecific process for converting 6-aminopenicillanic acid into the optically active azetidinone known intermediate of formula: CD.YCM.3F - 8 - SY-1757 OR "0

F H H II

'] 3 A ""' 'NH C> where R "represents a classical radical protecting the hydroxyl function and the absolute configuration at carbon atoms 1', 3 and 4 is R, R and R. These compounds are key intermediates for the synthesis of a large number of carbapenems and antibiotic penemes already described carrying a radical (R) -hydroxyethyl at position 6 of the carbapenem or penem nucleus and having the absolute configuration R and S (trans) at positions 5 and 6 The invention also relates to certain new intermediates used in this process.

More specifically / the subject of the present invention is an improved process for the preparation of the optically active intermediate azetidinone I which comprises the stages: (a) of converting, according to known procedures, 6-aminopenicillanic acid into an anhydro-pericillin of formula :

Y__fY

—Y C v ^ where X and Y each independently represent a radical CD.YCM.3F - 9 - SY-1757 chloro, bromo, iodo or phenylseleno (SeC5Hs); (b) reacting intermediate V with a reactant chosen between a Grignard reagent of formula R] MgX and an organolithic compound of formula

R11, where R1 represents a lower alkyl or aryl radical and X is as defined above, in an anhydrous inert organic solvent at a temperature of about 0 to -78 ° C, and then add acetaldehyde to exclusively form the formula intermediary:

OH

! * 1.

γ ° lia where X is as defined above; (c) convert the intermediate lia into the corresponding intermediate of formula: OR "/ Ar ^ SY °

Ilb 9

where R "represents a conventional radical protecting the hydroxyl function, very advantageously a bulky triorganosilyl radical such as t-butyldimethylsi-“ Γ lyl, t-butyldiphenylsilyl or triisopropylsilyl, and X

is as defined above; - d) subjecting intermediate Ilb to CD.YCM.3F - 10 - SY-1757 reduction in an inert solvent and isolating the 5,6-trans isomer thus obtained of formula OR "

f H H

Α'Λ_L * s

ITT

° Illb \ or R "is as defined above; (e) to open the thiazolidine cycle of the intermediate Illb to form an acetoxyazetidinone intermediate of formula î OR" 0

f H H H

A Λ i ^ 0CCH ^ p [Rj C0_H IV 2 and (f) oxidize the intermediate IV to remove the entity -methylcrotonate and form the desired optically active intermediate.

According to a variant of the process described above, the intermediate 11a can be reduced before the protection of the functional hydroxyl radical.

Formula intermediaries; s CD.YCM.3F - 11 - SY-1757 4 * · OR 'OR' I x tf J S «s .0

cf V 0 T

He III

where X represents a chloro, bromo, iodo or phenylseleno radical and R1 represents a hydrogen atom or a conventional radical protecting the hydro-xyl function are new compounds which are also the subject of the invention.

DETAILED DESCRIPTION OF THE INVENTION.

The present invention provides a significant improvement to the process already known for converting 6-aminopenicillanic acid into acetoxyazetidinone i> optically active I which is the key intermediary for the synthesis of various antibiotic carbapenems and penemes, in particular thienamycin which is a broad spectrum carbapenem of formula:

OH

sch2ch2nh2) - * - k

0 COOH

e

As already indicated, the known methods for preparing (8R) -hydroxyethyl-carbapenems and -penems by the 6-APA route comprise an α * aldolic condensation introducing the desired 6-hydroxyethyl radical. A process described in the literature consists in converting 6-APA to its 6-acetylated derivative, CD.YCM.3F - 12 - SY-1757 and then reducing the latter to the desired hydroxyethylpenicillin (JACS 103; 6765- 6767, 1981). The reduction ~ is however not stereospecific and the desired optical isomer must be isolated from a mixture of diastereoisomers. The direct hydroxyethylation of a 6-halopenicillin, 6,6-dihalopenicillin or 6,6-bis (phe-nylselenyl) penicillin is described, for example, in Chem. Pharm. Bull. 29 (10): 2899-2909 (1981), J. Org.

Chem. 42: 2960-2965 (1977), Heterocycles Γ7: 201-207 (1982) and Tetrahedron Letters 23 (39): 4021-4024 (1982), but this method has the disadvantage that the aldolic reaction on the intermediate penicillin is not not stereospecific and that it is necessary to separate the (8R) -hydroxyethyl-isomer desired before carrying out the other stages of the synthesis.

The present invention is based on the unexpected discovery that an aldolic condensation carried out on certain 6,6-disubstituted anhydropenicillins leads to the exclusive formation of a single stereoisomer, namely that of formula:

OH

Λ's! R R | κ? - "'N ........

Y

where X represents a halo or phenylseleno radical, which has the desired 5R, 6R, 8R stereochemistry. This stereospecific hydroxyethylation eliminates the need to separate the stereoisomers after this operation and together with the stereospecific reductive elimination of X under the preferred conditions in accordance with the invention greatly improves the efficiency of the synthesis of antibiotic-CD.YCM carbapenems and carbapenems. 3F - 13 - SY-1757 - ques by the way of 6-ΑΡΆ.

The general reaction scheme of the process of the invention is illustrated below in the case where a 6,6-dibromopenicillin is the starting compound: CD.YCM.3F - 14 - SY-1757

JW

Vf X 2

y-f î iA

w \ y—? N 'Ho

I Üi X

ε o

Ml ro m ta-- "xx ^ <-> u Λ U ° c œ o A 2

iH

(M -H

O m T θ 'x \ _ \ y y ’- z -, y1—' \" "- ^ \ _ 2 V — Z _ | S * °" 2 J-Λ / ^ ow / * °.; ts O \ i A x '' © c v Ή cj Ό H -H U M O î * m a in

? X

CM

υ

CM

CO I Ο X Ο. Ο _υ> \ cm o = u νι ο ο ') —Ü

Vf + J "! - · \ Η "t

, Wi I J

I \ ° + JJ \% \ ~ f -lu 0 Jv + l_L - \ s \ w H / SS, \ v \ - w— / V- ^ ^ o

Jv ^ ° = "y§ lr ^

A + Itt l M

Λ -H / V Λ “V3" * V c l: £ “0% S x Ό 0 '(L · u

U

CD.YCM.3F - 16 - SY-1757 - In the above process, 6-APA is first converted according to known techniques to a 1 6,6-dihaloanhydropênicilline or 6,6-bis (phenylselenyl) - intermediate anhydropenicillin of formula: —rr / --- vv where X and Y each independently represent a chloro, bromo, iodo or phenylseleno radical. The intermediates of formula V which are the starting compounds for the new reaction stages in accordance with the invention are known compounds or prepared according to known methods. These intermediates can be prepared by conversion of 6-APA to 6,6-dihalo-penicillanic acid or to the corresponding 6,6-bis (phenylselenyl) -penicillanic acid, by formation of a halide or mixed anhydride of l acid and then by reaction of the acid halide or anhydride with a tertiary amine leading to anhydropenicillin. British patent published 2,405,755A describes the preparation of various 6,6-dihalopenicillanic acids such as 6,6-dibromopenicillanic acid, 6-chloro-6-iodopenicillanic acid, 6-bromo-6-iodopenicillani acid -that and 6,6-diiodopenicillanic acid. The preparation of 6,6-bis (phenylselenyl) penicillins is described in 'Tetrahedron Letters 23 ^ (39): 4021-4024 (1982). The conversion of 6,6-dihalopenicillanic acids to the corresponding anhydropenicillins is explained, for example, in J. Chem. Soc. (C): 2123-2127, 1969, where the preparation of 6,6-dibromoanhydropenicillin is CD.YCM.3F - 17 - SY-1757 'specifically described. The E.U.A. 3,311,638 describes general techniques for the conversion of S penicillins to anhydropenicillins. The starting anhydropenicillins especially preferred for the process of the invention are 6, 6-dihaloarihydropéni-cillines, especially 6,6-dibromoanhydropenicillin and 6-bromo-6-iodoanhydropenicillin, and specifically 6 , 6-dibromoanhydropenicillin.

The starting arihydropenicillin is subjected to an aldolic condensation leading to the desired hydroxyethyl intermediate of formula: f ““ R R | y— iy lia where X represents a chloro, bromo, iodo or phenylazo radical and especially bromo and whose absolute configuration is 5R, 6R, 8R. This operation is the key stage of the process of the invention since the aldolic condensation on the intermediate anhydropenicillin exclusively leads to the optically active isomer sought, that is to say to the stereoisomer having the cis configuration with carbon atoms. 5 and 6 and * 'carrying a (8R) -hydroxyethyl radical in position 6.

This unexpected stereospecific aldolic condensation eliminates the need to separate the diastereoisomers as it is necessary to do in conventional methods and therefore greatly increases the practical interest = in the synthesis of carbapenems and penemes by the 6-APA route.

î Aldolic condensation can be performed CD.YCM.3F - 18 - SY-1757 e in much the same way as reactions already known with penicillins, see, for example? Org. Chem. 42 (18): 2960-2965 (1977), An enolate is first formed from 6,6-dihaloanhydropenicil-line by a metal-halogen exchange at a temperature below about 0eC, for example from 0 to -78 ° C., using an organolithic reagent or a Grignard reagent and the resulting enolate is then reacted in situ with an excess of acetaldehyde to give the hydroxyethylated product.

The aldolic reaction is carried out in an inert anhydrous organic solvent, for example methylene chloride, chloroform, tetrahydro-furan, diethyl ether, toluene, dioxane, dimethoxyethane or their mixtures at temperatures below 0eC and preferably less than about -20ÖC. The enolate is formed using an approximately equivalent molar amount of organolithic reagent or Grignard reagent.

The preferred organolithic reagents are those of formula R 1 Li, where R 1 represents a lower alkyl radical, namely C 1 -C 6 alkyl or an aryl radical, namely a C 6 -C 10 aryl radical such as phenyl. An example of a suitable organolithic reagent is n-butyllithium. The Grignard reagent is preferably of formula RiMgX, where Ri represents a C 1 -C 6 alkyl radical or C 6 -C 10 aryl and X represents a chloro, bromo or iodo radical. The preferred Grignard reagents are methylmagnesium bromide and methylmagnesium chloride. In a preferred embodiment, methylmagnesium chloride is used at a temperature of about -40 ° C to -45 eC. In another preferred embodiment, methylmagnesium bromide is used at? a temperature of around -20eC. After the formation of CD.YCM.3F - 19 - SY-1757 - the enolate, a molar excess of acetaldehyde is added for the formation of the desired hydroxyethyl isomer. c Intermediate lia can then be subject to reduction for the formation of intermediate —Ιγ

Ilia or, alternatively and preferably, the intermediate lia can be converted first into the corresponding intermediate anhydropenicillin whose hydroxyl radical is protected by a conventional radical protecting the hydroxyl function and then be reduced to the hydroxy- protected OR "

I H H

—N —W '

Illb where R "represents a conventional radical protecting the hydroxyl function. If the reduction is carried out directly on the intermediate lia, the hydroxyl radical of the product Ilia is protected for the formation of the intermediate Illb before the subsequent opening of the cycle of thiazolidine.

; The protection of the hydroxyl radical is carried out according to known techniques by means of radi-r. conventional waters protecting the hydroxyl function CD.YCM.3F - 20 - SY-1757 * which are well known to the specialist. Protection of the hydroxyl radical of intermediate lia or Ilia is desirable to prevent side reactions and lower yields in the subsequent stages of the reaction sequence, for example, degradation of the cycle by mercuric salt. Suitable radicals to protect the hydroxyl function are, for example, acyl radicals, such as benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, p-nitroben-zyloxycarbonyl and 2,2,2-trichloroethoxycarbonyl, aralkyl radicals such as benzyl, benzhydryl or trityl p-nitrobenzyl or triorgano-silyl radicals such as trialcoyliC ^ -Cg) silyl (such as trimé-thylsilyl, triethylsilyl, triisopropylsilyl, isopro-pyldimethylsilyl, t-butyldimethylsilyl, methyldiiso-propylsilyl or methyyl) or methyilyl) triphenylsilyl, tri-p-xylylsilyl) or triaral-coylsilyl (such as tribenzylsilyl). Examples of these and others which are suitable for protecting hydroxyl function and methods for forming and eliminating them are well known, see, for example, Protective group in Organic Synthesis, T.W. Green, John Wiley and Sons, New York, 1981, chapter 2.

Any conventional radical protecting the hydroxyl function can be used for the reductive elimination of the radical X, but it was unexpected to discover that a bulky triorganosilyl radical protecting the hydroxyl function such as t-butyldi-methylylylsilyl, t-butyldiphenylsilyl or triisopropylsilyl , leads to the substantially exclusive formation (for example for about 95%) of the desired isomer trans Illb, while other radicals protecting the hydroxyl function or the unprotected intermediate 11a lead to the simultaneous formation of the iso-> cis unwanted mother in sufficient quantity for a CD.YCM.3F - 21 - SY-1757 r fractionation stage to become necessary. Consequently, in a preferred embodiment of the invention, the intermediate 11a is converted into the corresponding intermediate Ilb whose hydroxyl function is protected and in which R "represents a bulky triorganosilyl radical, preferably t-bu-tyldimethylsilyl , t-butyldiphenylsilyl or triisopro-pylsilyl, after which this intermediate is subjected to the reaction with a view to the substantially stereo-selective formation of the trans intermediate Illb.

The radical protecting the hydroxyl function which is chosen must be a radical which is easy to remove at a later stage of the process. Protective triorganosilyl radicals are advantageous (moreover, some of these radicals, for example bulky triorganosilyl radicals such as triisopropylsilyl, t-butyldiphenylsilyl or t-butyldimethylsilyl are preferred for a substantially stereo-specific reduction) because these radicals can be easily eliminated under moderate conditions, for example by reaction with methanolic HCl or with the fluoride ion (for example with tetra-n-butylammonium fluoride / tetrahydrofuran), without destruction of the sensitive Jb-lactam nucleus. Silylation can be carried out using a suitable silylating agent (for example silyl chloride or silyl triflate) in an inert organic solvent, such as methylene chloride, tetrahydrofuran, dio-xane, dimethoxyethane , chloroform or diethyl ether, and in the presence of a base, for example an organic base such as pyridine, 2,6-lutidine, imidazole or triethylamine. Silylation can be carried out over a wide temperature range, but preference is given to temperatures of about -40 ° C; at around + 5eC. In a preferred embodiment, CD.YCM.3F - 22 - SY-1757 the hydroxyl radical of intermediate lia or Ilia is silylated by means of triisopropylsilyl triflate, t-butyldiphenylsilyl triflate or t-butyldimethylsilyl triflate in methylene chloride, tetrahydrofuran, chloroform, toluene or diethyl ether, but more advantageously in tetrahydrofuran or methylene chloride, at a temperature in the region of 0 ° C.

Intermediate 11a or hydroxy-protected intermediate Ilb is subjected to reduction eliminating the halogen or phenylseleno radical and forming the desired compound 5R, 6S

f H H

s Y ° oJ - »-

III

where R 'represents a hydrogen atom or conventional radical protecting the hydroxyl function, which is preferably a bulky triorganosilyl radical such as triisopropylsilyl, t-butyldiphenylsilyl or t-butyldimethylsilyl. The reduction can be carried out using a chemical reducing agent, such as the zinc-silver couple, the zinc-copper couple, stannous iodide, tin hydride, zinc amalgam, zinc or zinc activated with an acid (for example hydrochloric acid or acetic acid) or else by catalytic hydrogenation. It is usual to use an inert solvent such as tetrahydrofuran, diethyl ether, methanol, ethanol, isopropanol, acetic acid, mixtures of ether and alcoholic solvents, etc. In a preferred embodiment, CD.YCM.3F - 23 - SY-1757 - uses the zinc-silver couple in a THF / methanol solvent system. In another preferred embodiment S, zinc activated with an acid is used which is preferably hydrochloric acid or acetic acid. The reduction can be carried out over a wide temperature range, for example from -45 ° C to room temperature. In general, the reduction gives the specially desired trans isomer (5R, 6S) as the predominant product with at most minor amounts of the less desirable cis isomer. As indicated above, if the intermediate 11a is converted into a hydroxy-protected intermediate Ilb, where R "represents a bulky triorganosilyl radical such as triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, the reduction of Ilb is essentially stereospecific and gives almost exclusively the desired trans isomer, therefore, under these preferred conditions, the reduction product can be used directly for subsequent reactions without the need to first separate the unwanted cis isomer formed simultaneously.

After the reduction, the intermediate anhydropenicillin II, if necessary after protection of the hydroxyl radical, is converted by known reactions into the desired intermediate acetoxyazetidinone. Thus, in the especially preferred embodiment, the hydroxy-protected intermediate Illb, which * 'has the desired chirality at carbon atoms 5, 6 and 8, is subjected to degradation of the thiazolidine ring, for example by means of mercuric acetate in acetic acid, to give the intermediate CD.YCM.3F - 24 - SY-1757 'OR "Ο jg H OCCH-

R R

C02H

IV

where R "represents a conventional radical protecting the hydroxyl function, and this intermediate IV is then oxidized to the optically active intermediate I desired. The degradation of the thiazolidine cycle is described in the literature and can be carried out, for example, by reaction of the intermediate IIIb in acetic acid or in a mixture of acetic acid and an inert organic solvent such as tetrahydrofuran or dioxane with a mercuric salt such as mercuric acetate or mercuric chloride at a temperature d '' about 0 ° C to 40 ° C.

The elimination of the crotonate entity is carried out by oxidation of intermediate IV. Ozone-lysis (for example ozone in methanol) makes it possible to directly oxidize IV acid via intermediate I. Chemical oxidants such as potassium permanganate, potassium permanganate with a transfer catalyst phases, potassium permanganate with sodium periodate and ruthenium tetroxide with sodium periodate generally require that the carboxylic acid radical of compound IV be protected before oxidation, for example by conversion to ester or anhydride.

The above reaction can obviously, thanks to a judicious choice of solvents, be carried out without. isolation of one or more of the CD.YCM.3F - 25 - SY-1757 r sequence intermediaries. Alternatively, when possible, the intermediates can be isolated in a crystalline state and possibly purified, for example by recrystallization, before the execution of the subsequent reaction stages.

It is obvious to the specialist that the process of the invention, although described with regard to the production of acetoxyazetidinone I, can be easily modified for the preparation of other intermediate azetidinones of formula OR "! N

A _i> * L

S Rj

J WH

where L represents a classical leaving radical. For example, the intermediate Illb above can be subjected to chlorolysis (CI2 / CH2CI2, -15eC) to give the compound of formula QR "1 H h A to C0C1 which can be oxidized, after conversion to the acid or corresponding ester, as described above with respect to the corresponding acetoxy-derivative, to give the chloro-intermediate CD.YCM.3F - 26 - SY-1757 OR "

f H H

y i n o

The intermediate (R) -hydroxyethylazetidinone obtained in accordance with the invention, that is to say the intermediate I or a compound analogous thereto, such as the chloro-intermediate above, easily carried out by known methods to thienamycin and other carbapenems and penemes having useful anti ibacterial activity.

The following examples in which the temperatures are given in ° C., unless otherwise indicated, illustrate the invention without limitation. EXAMPLE 1.-

Preparation of (4R.) - acetoxy- (3R) - / * (11 R) - (t-butyl-dimethylsilyloxy) ethyl ^ 7-2-azetidinone from 11arihydro-6,6-dibromopenicillin

Br OSi -f-

Br - l ^ 'Y0 _ ^ OAC

j — î — l - * xy

o 'Y A-NH

G

CD.YCM.3F - 27 - SY-1757 A. Arihydro-6,6-dibromopenicillin

Br Br -—rf_ — rr J — N— J — N-V1 ο oi co2h

Triethylamine (58.4 millimoles, 8.00 ml) is added dropwise to a cold solution (ice and methanol bath) of 6,6-dibromopenicillinic acid (20.00 g, 55.56 millimoles) in dichloromethane (200 ml) which is stirred for 15 minutes. Trifluoroacetic anhydride (8.40 ml, 61.2 millimoles) is added dropwise to the solution. The latter is stirred for 30 minutes, then pyridine (4.8 ml, 61.2 millimoles) is added dropwise. The mixture is stirred for 30 minutes at -10 °, then for 18 hours at 5th. The mixture is washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate and brine, then dried (anhydrous magnesium sulfate). The residue obtained by evaporation of the solvent is redissolved in ethyl acetate and activated carbon is added thereto to then isolate the compound mentioned in the title PF PF 102-103 ° (methanol) (16.1 g, 47.2 millimoles, yield 85%).

1 H NMR (CDCI3, 80 MHz) S s 5.80 (1H, s, H-5), 2.21 (3H, s, CH3) and 2.15 ppm (3H, s, CH3) * IR (CH2Cl2) max · 1800 (strong, C = 0 of P-lactam), 1708 (strong, C = 0 of lactone) and 1640 cm "·! (Weak, olefin);" + 88'9 ° <£ * ° '144' CH3OH ); CD.YCM.3F - 28 - SY-1757 * Analysis for C8H7NC> 2SBr2:

Calculated: C, 28.17, H, 2.07, N, 4.10;

Found: C, 28.08, H, 1.98, N, 4.06%.

B, Anhydro-6 ° <-bromo-6 ^ £ (11R) -hydroxyethyl J -penicillin ·

OH

Br! Br

"-I — Y

Anhydro-6,6-dibromopenicillin (15.02 g, 44 millimoles) is dissolved in cold tetrahydrofuran (450 ml) and a 2.85 M solution of methylmagnesium bromide is added dropwise (18.0 ml, 51.3 millimoles) in ether and the mixture is stirred at -78 ° for 20 minutes. Excess acetaldehyde (25 ml, 0.45 mole) is added to the resulting magnesium enolate and the mixture is stirred for 20 minutes. The cooling bath is removed and 1N aqueous hydrochloric acid (70 ml) and ether (30 ml) are added to the reaction mixture. The aqueous phase is separated and extracted with ether (2 x 200 ml). The organic phases are combined, washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate and brine and dried (anhydrous magnesium sulfate).

The solvent is removed to obtain the compound announced in

V

title ï (13.08 g, 42.7 millimoles, yield 97%) which is in the form of an oil.

1 H NMR (CDCI3) δ: 5.61 (1H, s, H-5), 4.28 (1H, q, 'J = 6.0, Hl'), 2.21 (3H, s, CH3), 2 , 16 (3H, s, CH3) 1.64 (1H, si, OH) and 1.31 ppm (3H, d, J = 6.0 Hz, CH3); IR (CH2CI2) ^ max! 3560 (medium, OH), 1785 (strong, C = 0 CD.YCM.3F - 29 - SY-1757 of y2> -lactam), 1710 (strong, C = 0 of lactone) and 1635 cm “l (medium, olefin); / "o (722 + 83.8 ° (c - 0.128, methanol); D ~

Analysis for C10Iïl2NO3SBr2:

Calculated C C, 39.23, H, 3.95, N, 4.57;

Find ; C, 38.31, H, 4.63, N, 4.61%.

C. Anhydro-6o <-bromo-6ß [(11 R) - (t-butyldimethyl-silyloxy) ethyl ./pénicilline 0H OSi -f- ^ -N- ^ ^ N ^

Is added to a cold solution (ice bath) of anhydro-6 o <-bromo-6fi> - [(11 R) -hydroxyethyl J -penicillin (6.0 g, 19.6 millimoles) in methylene chloride ( 60 ml) first 2,6-lutidine (4.50 ml, 39 millimoles), then dropwise t-butyldimethylsilyl triflate (7.8 ml, 34 millimoles). The mixture is stirred (5 °) for 1 hour, then washed with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate and brine. The resulting organic phase is dried (anhydrous magnesium sulfate), diluted with an equal volume of a mixture of ether and petroleum ether (1: 2) and added with activated charcoal. The solid residue obtained by evaporation of the solvent is redissolved in hot hexane and crystallized to collect 5.35 g of the title compound. The mother liquor is concentrated, added with activated charcoal and crystallized in the cold (5th, 1.28 g). By combining the two crops, the hydro-derivative CD.YCM.3F - 30 - SY-1757 £ protected xylate (6.63 g, 15.7 millimoles, yield 80.7%), PP 116-117 ° ( methanol).

(CDC13) 6; 5.53 (1H, s, H-5), 4.27 (1H, q, J = 6.1 Hz, H-111), 2.20 (3H, s, CH3), 2.13 (3H, s, 013), 1.28 (3H, d, J = 6.1 Hz, CH3), 0.91 (9H, s, t-butyl), 0.09 (3H, s, CH3) and 0.07 ppm (3H, s, CH3)? IR (CH2CI2) "Ό max: 1785 (strong, C = 0 of Jb-lactam), 1700 (strong, C = 0 of lactone) and 1635 cm ~ l (medium, olefin); /" CXJ22 + 119.6 ° (c = 0.14, methanol);

Analysis for CigH27N03SBrSi:

Calculated: C, 45.60, H, 6.45, N, 3.32;

Found: C, 46.38, H, 6.02, N, 3.23%.

D. Anhydr0-6 o <- [(! '£) - (t-butyldimethyls ilyloxy) -ethyl ./pénicilline

I I

OSi-T OSi - + - J— »y / -« - y

Is added to a solution of anhydro-6 oc -bromo-6β> - [(1 * R) - (t-butyldimethylsilyloxy) ethyl ^ -penicillin (1.00 g, 2.38 millimoles), in a mixture of 25% tetrahydrofuran-methanol (25 ml) cooled to -45 °, Zn (Ag) (10 g) [Zinc-silver couple prepared from 1 part of silver acetate and 11.7 parts of zinc_7. The mixture is stirred until all the starting compound has been consumed (thin layer chromatography, Rf = 0.4, 2% acetonitrile in dichloromethane), then it is introduced by filtration through a layer of Celite in a cold aqueous solution CD.YCM.3F - 31 - SY-1757 i of IM ammonium chloride. The phases are stirred, separated and the aqueous phase is extracted with ether (3 x 10 ml). The organic phases are combined and washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate and brine, then dried (anhydrous magnesium sulfate). By evaporation of the solvent,

B

an oil which is crystallized under vacuum (815 mg, 2.38 millimoles, yield 99.6%). HPLC analysis of the solid reveals the following ratio: starting compound 0.70%, cis isomer 2.51% and compound announced in the title 96.79%; M.p. 56-57 ° (methanol).

RMnIh (CDC13) <5: 5.29 (1H, d, J = 1.8, H-5), 4.34 (1H, dq, J = 6.3, J = 6.5 Hz, Hl ') , 3.52 (1H, dd, J = 3.5 Hz, £ “1.8 Hz, H-6), 2.17 (3H, s, CH3), 2.08 (3H, S, CH3), 1.25 (3H, d, J = 6.3 Hz, CH3), 0.89 (9H, s, t-butyl) and 0.09 ppm (6H, s, CH3); IR (CH2CI2) max: 1775 (strong, C = 0 of Jb-lactam), 1695 (strong, C = 0 of lactone) and 1635 cm-1 (medium, olefin); [oij22 + 42.8 ° (c. = 0.114, methanol);

Analysis for C16H27NC> 3SSi:

Calculated: C, 56.10, H, 8.24, N, 4.09, S, 9.38;

Found: C, 56.65, H, 7.82, N, 4.07, S, 9.04%.

The corresponding isomer 6 - ^ / 3- (11] ¾) is isolated in the form of an oil: (CDCI3) <5: 5.35 (1H, d, J = 4.6 Hz, H-5) , 4.31 (1H, dq, J = 6.0, J = 9.4, H-l '), 3.83 (1H, dd, J = 4.6, J = 9.4, H-6 ), 2.18 (3H, s, CH3), 2.08 (3H, s, CH3), 1.23 (3h, d, J = 6.0, CH3), 0.89 (9H, s, t -butyl), 0.10 (3H, s, CH3) and 0.06 ppm (3H, s, CH3); , IR (CH2C12) max: 1785 (strong, C = 0 of Jb-lactam), 1695 (strong, C = 0 of lactone) and 1635 cm ~ l (medium, olefin)? CD.YCM.3F - 32 - SY-1757 £ <* J22 + 171.2 ° (£ = 0.084, methanol).

2 E. Acid ex - [(3S) - £ (1 '£) - (t-butyldimethylsilyloxy) -ethyl _7- (4S) -acetoxy-2-azetidinone-l-yl] -Jb-methylcrotonic oli-J- OSi - | - ^ '- pi'εγ_ ^ J'l "rfoh] —Ny Nv'P's-

C02H

Mercuric acetate (14 g, 44 millimoles) is added at 22 ° to a solution of 6-anhydro (- £ (1'R) - (t-butyldimethylsilyloxy) ethyl_7 penicillin (5.00 g, 14.6 millimoles) in acetic acid (75 ml) which is stirred for 24 hours, additional mercuric acetate (9.3 g, 29 millimoles) is added to the mixture and stirring is continued for another 24 hours. The reaction mixture is filtered through a layer of Celite and the solid is washed with acetic acid, the filtrate is diluted with water (150 ml) and extracted with ether (5 x 40 ml) The organic extracts are combined, washed with water (3 x 40 ml) and brine, then dried (anhydrous magnesium sulphate) and added with charcoal. oil which is crystallized under vacuum (5.33 g, 13.8 millimoles, yield 95%), PP 119-120 ° (dichloromethane / petroleum ether 9: 1).

1 H NMR (CDCI 3) Ô î 6.32 (1H, d, J = 1.4 Hz, H-4), 4.24 (1H, center of 5 lines, J = 6.0, H-1 '), 3 , 20 (1H, dd, £ -1.4 Hz, J = 5.8 Hz, H-3), 2.24 (3H, s, CH3), 2.05 (3H, s, CH3C02), 1, 97 (3H, s, CH3) / 1 ”29 (3H, d, J = 6.3, CD.YCM.3F - 33 - SY-1757 CH3), 0.86 (9H, s, t-butyl), 0.08 (3H, s, CH3) and 0.05 ppm (3H, s, CH3) * IR (CH2Cl2) ^ max1770 (strong, C — O from Ji> —lactam), 1745 (medium, CH3C = 0), 1690 (medium, CO2H) and 1620 cm-1 (weak, olefin); + 18.9 ° (c = 0.088, methanol);

Analysis for C18H31NO6S1:

Calculated: C, 56.07, H, 8.10, N, 3.63;

Found s C, 56.00, H, 8.25, N, 3.73%.

F. (4R) -Acetoxy (3R) ~ Ç (11 R) - (t-butyldimetbylsilyl-oxy) ethyl 7-2-azetidinone I ° | 1+ fV- +

/ r'x, _-> ° ÂC

JR m - _ ^ ir r J.

0-r — N A — N s / C02H C02C02And f! 1 + Αλ_s0kc

IR RI

- ^ j

Ethyl 2-ethoxy-1- (2H) -quinoline-carboxylate (EEDQ, 1.63 g, 6.20 millimoles) is added to an "X - (3R) - /" acid solution ( 1 'R) - (t-butyldimethylsilyl-oxy) ethyl _7- (4R) -acetoxy-2-azetidinone-l-yl J ^ - ^ - methyl-crotonic (2.0 g, 5.2 millimoles) in dichloro -methane (30 ml) at -15 ° (ice and methanol bath) The cooling bath is removed and the CD.YCM.3F - 34 - SY-1757 is stirred for 18 hours at 22 °. washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate and brine and dried (anhydrous magnesium sulfate). By evaporation of the solvent, a mixed anhydride is obtained (2, 14 g, yield 93.3%) in the form of a derivative whose carboxylic acid radical is protected. 1 H NMR (CDCl 3) S: 6.23 (1H, d, £ = 1.4, H-4), 4 , 32 (2H, q, J-7.1, CH2CH3), 4.05-4.39 (1H, m, £ = 6.1, H-l '), 3.23 (1H, dd, J = 1.4, £ = 6.1, H-3), 2.25 (3H, s, CH3), 2.06 (3H, s, CH3CO), 1.17 (3H, s, CH3), 1, 35 (3H, t, £ = 7.1, CH3CH2), 1 , 29 (3H, d, £ = 6.1, CH3), 0.86 (9H, s, t-butyl), 0.08 (3H, s, CH3) and 0.05 ppm (3H, s, CH3 ); IR (CH2CI2) max: 1800 (strong, mixed anhydride), 1775 (strong, C = 0 of lactam), 1750 (strong, C = 0 of acetate) and 1725 crrr1 (weak, olefin).

The resulting mixed anhydride (2.10 g, 4.76 millimoles) is dissolved in dichloromethane (30 ml), cooled to -78 ° (acetone and dry ice bath) and ozonolysed until disappearance of the starting compound (1.5 hours). The cold (-78 °) solution of the ozonide is reduced with dimethyl sulfide (6 ml) and stirred at room temperature for 1.5 hours. Methanol (30 ml) is added, followed by 2,6-lutidine (1.2 ml). The mixture is stirred at 22 ° for 2 hours, diluted with ether, washed with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate and brine and dried (anhydrous magnesium sulfate). By evaporation of the solvent, the title compound is obtained (1.31 g, 4.56 millimoles, yield 95%) which is in the form of a white solid, PP 104-106 ° (ether / petroleum ether l / l) [PP cited in the literature 104-106 ° J.

[oij ^ + 47.4 ° (c = 0.136, chloroform).

CD.YCM.3F - 35 - SY-1757 0 Rotating power 48.8e (c = 0.41, chloroform) according to Chem. Pharm. Bull. (Tokyo), 29, 2899 (1981) J, EXAMPLE 2, - 6- oc -Bromo-6 fî> - £ (11E) -Ί-hydroxyethyl J7anÎiy ^ roPÔni ~ cilline and 6 oc-bromo-6 (1'R ) -t-butyldimethylsilyl-oxy) ethyl_7anhydropenicillin illustrating aldolic condensation at relatively high reaction temperature (-20 °) OH „“ I Br ΒΓ-UY ° 11 CH3MgBr? J_N-L 2) CH3CH0 J-N- q -20 ° O 'osi + CH2C12 ß-N-

REACTANTS

Anhydropenicillin 10.23 g (0.03 mole)

12.21 ml bromide (0.0348 mole, 16% methylmagnesium excess, 2.85M solution in ether,

Aldrich)

Acetaldehyde 6.6 g or 8.4 ml (0.15 mole, d. 0.788, Aldrich) CD.YCM.3F - 36 - SY-1757, THF 150 ml (dried on molecular sieve)

TfOSx ^ —- 11.54 g or 10.02 ml (distilled, N 0.0436 mole, d. 1.151) \ 2.6-Lutidine 6.42 g or 6.98 ml (0.006 mole, d. 0.92 , Aldrich)

Dichloromethane 100 ml (dried on molecular sieve).

OPERATING MODE

Methyl magnesium bromide (12.21 ml) is added dropwise over 10 minutes to a solution of anhydro-6,6-dibromopenicillin (10.23 g) in dry THF (150 ml) cooled to -20 ° while maintaining the temperature between -15 ° and -20 °. The resulting solution is stirred at -20 ° for 10 minutes, then acetaldehyde (8.4 ml) is added to it initially dropwise over 5 minutes, maintaining the temperature between -15e and -20e. The solution is stirred at -20 ° for 15 minutes. Saturated ammonium chloride (10 ml) is added, followed by water (80 ml) to the reaction mixture. The mixture is then extracted with ethyl acetate (150 ml, 50 ml). The extract in ethyl acetate is washed with brine (twice, 100 ml each time), dried over anhydrous sodium sulfate and concentrated to give an oil (8.9 g, 97%). HPLC analysis * indicates 92% of the cis isomer, no trans isomer and 8% of impurities.

CD.YCM.3F - 37 - SY-1757 * Column JJ * Porasil (Waters)

Solvent 3% CH3CN / CH2CI2 Flow rate 90 ml / hour UV detection at 275 nm

Attenuation 0.2

The above crude oil is dissolved in dry dichloromethane (100 ml) cooled to 0 °. 2,6-lutidine (6.98 ml) is added thereto, then dropwise t-butyldimethylsilyl trifluoromethanesulfonate (10.02 ml) over 20 minutes while the temperature is maintained at 0 ° -5e. The resulting solution is stirred at 0 e-5 e for 1 hour. Thin layer chromatography (silica, ether-petroleum ether 1: 1, I2) indicates that the reaction is complete. The reaction mixture was washed with IN hydrochloric acid (100 ml), saturated sodium bicarbonate (100 ml) and brine (100 ml), respectively, then dried over anhydrous sodium sulfate and concentrates it to - collect a dark oil which gradually solidifies. The oil is dissolved in hot petroleum ether, added with activated charcoal and the solution is concentrated to dryness (14 g). This crude solid is redissolved in hot isopropanol (70 ml), the solution is diluted with water (35 ml) while it is still hot, it is cooled to 0 ° and the whole is filtered. The filter cake is washed with an isopropanol: water 2: 1 mixture and dried in a vacuum desiccator.

. Production 7.0 g (55.5% over the two stages).

CD.YCM.3F - 38 - SY-1757 EXAMPLE 3.- 6 ο (-Bromo-6jb- £ (1 lE) ~ (t-butyldimethylsilyloxy) ethyl_7 ~ anhydropenicillin illustrating the use of methylmagnesium chloride as Grignard reagent

OH

Br |

Br -I-f 'vf ° 11 ÇH3Mgci Ύ °

J — N-L THF 0 ^ Y

I -45th - -40 ° _ _ I., qsi “Γ ^ Ί I Br

Tfosi 4 * / "Ό ^ s n # * -> 5 \

2,6-lutidine M

toluene yy

REACTANTS

Anhydropenicillin 34.1 g (0.01 mole)

39.6 ml chloride (0.116 mole), 16% methylmagnesium excess, 2.9M solution in THF)

Acetaldehyde 28 ml or 22 g (0.5 mole, d. 0.788) THF 350 ml (dried on molecular sieve) 2,6-Lutidine 23.3 ml or 21.4 g (0.2 mole, d. 0, 92, dried on KOH) CD.YCM.3F - 39 - SY-1757

Tfosii "32 g or 27.6 ml (0.12 mole, d. 1,151) tr

Toluene 800 ml

OPERATING MODE

A solution of arihydro-6,6-dibromopenicillin (34.1 g) in dry THF (350 ml) is cooled to -45 ° and methylmagnesium chloride (39.6 ml) is added dropwise ) in 20 minutes keeping the temperature below -40 °. The resulting solution is stirred at -45 ° to -40 ° for 10 minutes and acetaldehyde (28 ml) is added to it initially dropwise over 5 minutes, while the temperature is kept below -30 °. The solution is stirred at -40 ° for 15 minutes. Saturated ammonium chloride (35 ml) is added, followed by water (400 ml) to the reaction mixture. The reaction mixture is extracted with toluene (350 ml and 150 ml). The toluenic extract is washed with brine (twice, 300 ml), dried over anhydrous magnesium sulfate and concentrated to a volume of approximately 100 ml. Toluene (300 ml) is added to the concentrated solution and then the solution is concentrated continuously to about 300 ml. Analysis by HPLC * indicates a purity of 92% and does not reveal a trans isomer.

* Porasil column (Waters)

Solvent 3% CH3CN / CH2CI2 ** Flow rate 90 ml / hour UV detection at 275 nm

Attenuation 0.2

The toluene solution is cooled to 0 ° and 2,6-lutidine (23.3 ml) is added to it, then the triflate (27.6 ml) dropwise over 15 minutes while CD.YCM.3F - 40 - SY-1757 maintains the temperature at 0-5 “. The resulting solution is stirred at 0 ° for 1 hour. The mixture is examined by thin layer chromatography (silica gel, petroleum ether jether 1: 1, 12 ^ · add water (250 ml) to the reaction mixture and the pH is adjusted between 2.5 and 5 0.0 with concentrated hydrochloric acid (about 8 ml) The organic layer is separated, water (250 ml) is added to the organic layer and the pH is adjusted to 8.0 with hydroxide 1% sodium (about 10 ml) The organic layer is washed with brine (2 x 250 ml), added with activated charcoal (15 g) and concentrated to about 50 ml. Isopropanol (200 ml) and water dropwise (100 ml) to the concentrate which is stirred. 100 ml of solvent is removed under reduced pressure to obtain a dispersion which is cooled to 0 ° and stirred for 0.5 hour and filtered The filter cake is washed with an isopropanol ice water: 2: 1 mixture (80 ml) and dried in a vacuum desiccator Production 29.0 g (69%). PP 95-100 ° C. The crude product is recrystallized by saying solvent in toluene (150 ml), adding activated carbon, concentrating the filtrate as much as possible, adding isopropanol (200 ml), then dropwise water (100 ml) under cooling in ice and shaking. The precipitated product is collected by filtration and washed with an ice-cold isopropanol: water 2: 1 mixture and dried in a vacuum desiccator. Production 21.0 g (50%).

Mp 104-108 °.

CD.YCM.3F - 41 - SY-1757 EXAMPLE 4.- l · '- 6 <* -Ç (1 lR) - (t-butyldimethylsilyloxy) ethyl_7-anhydropenicillin illustrating the reduction by zinc / acetic acid Y' +

Zn / Ch3C00H ζ S Y °

/ - * - Y -20 - -15 0 ^ ~ N Y

OSi + _ [^ s ^ oJ — h — y

REACTANTS

Anhydropenicillin 42.0 g (0.01 mole)

Zinc powder 42.0 g (0.65 mole, Anachemia)

Acetic acid 11 ml or 11.54 g (0.19 mole,, · d. 1.049, glacial acid) * · Methanol 1000 ml

OPERATING MODE

11 arihydro-6 <* -bromo-6y3- [(l'R) -hydro- „xyethyl_7penicillin (42 g) is suspended in methanol (100 ml) in a three-necked flask of CD.YCM. 3F - 42 - SY-1757 2000 ml fitted with a mechanical stirrer, a thermometer, an intake bulb and nitrogen inlet and outlet tubes. The reaction mixture is cooled to -20 ° and the zinc powder (42 g) is added thereto, then acetic acid (11 ml) slowly. The resulting mixture is stirred at -25 ° to -15 ° for 0.5 hour. Thin layer chromatography (silica, *, ether: petroleum ether 1: 3, 12 or molybodate solution) indicates that the reaction is complete. By filtration through Celite, the reaction mixture is added to saturated ammonium chloride (100 ml) and the Celite is washed with methylene chloride. The filtrate is diluted with water (500 ml) and extracted with methylene chloride (1000 ml and 500 ml). The methylene chloride extract is washed with brine (1000 ml), dried over anhydrous magnesium sulfate and concentrated to an oil (34 g, 100% crude) which gradually crystallizes. Analysis indicates the presence of 83.3% trans isomer, 5.7% cis isomer and 11% impurities.

EXAMPLE 5, -

Preparation of anhydro 60C- and 6Jb ~ [(l'gi) -hydroxyéthyl_7pénicilline

OH

OH .

Br f Λ "ρΤ! R °

s — V c / -n_4Y

M

CD.YCM.3F - 43 - SY-1757

Jk, _γ ° R K | oJ — N — y

Zn (Ag) (4.2 g) is added to a cold solution (ice and methanol bath) of 6-anhydro-6 <X-bromo-6 / 3- / "(1 'R) -hydroxyethyl_7 penicillin ( 4.20 g, 13.7 millimoles) in methanol (40 ml) and the mixture is stirred for 15 minutes, additional Zn (Ag) (1.1 g) is added and the mixture is stirred for 10 minutes. By filtration through a Celite column, the liquid phase of the suspension is introduced into cold concentrated aqueous ammonium chloride, the solid is washed with ether and the two phases are separated. The aqueous phase is extracted with ether (2 x 20 ml) The ethereal extracts are combined and washed successively with 1N aqueous hydrochloric acid, water, 1M aqueous sodium bicarbonate and brine, then dried. residue from evaporation of the solvent in a cold mixture of petroleum ether and ether 9: 1 to obtain the 6 λ isomer (1.3 g), 5.7 millimoles, yield 42%) (it is advisable to '' observe that the reaction conditions are not opt and that the repetition of the experiment at -50 ° leads to a yield of isomer 6 "of 56.6%) which is in the form of a white solid. Mp 173-174 ° (dichloromethane / ether 2/8).

1 H NMR (CDCl3) â s 5.28 (1H, d, J = 1.7, H-5), 4.35 (1H, quintuplet, J = 6.2 Hz, H-1), 3.57 ( 1H, dd, J = 6.2, J = 1.7, H-6), 2.19 (3H, s, CH3), 2.11 (3H, s, CH3), 1.72 3 (1H, si, OH) and 1.40 ppm (3H, d, J = 6.3, CH3) 'IR (CH2Cl2) "Omax: 3500 (weak, OH), 1775 (strong, C = 0 v CD.YCM.3F - 44 - SY-1757 of ^ / ¾-lactam), 1695 (strong, C = 0 of lactone) and * 1635 cm ~ l (medium, olefin);

Analysis for C10Hl3NO3S:

Calculated: C, 52.84, H, 5.76, N, 6.16;

Found: C, 52.86, H, 5.72, N, 6.08%.

The cold mixture formed in ether / petroleum ether 19 is evaporated and the pure 6P "isomer is separated by preparative thin layer chromatography (2% acetonitrile in dichloromethane).

1 H NMR (CDCI3) Ô: 5.40 (1H, d, J = 4.6, H-5), 4.36 (1H, dq, J = 6.1, J = 9.0, H-1) , 3.74 (1H, dd, J = 9.0, J = 4.6, H- 6), 2.19 (3H, s, CH3), 2.25-1.90 (1H, si, OH ), 2.09 (3H, s, CH3) and 1.27 ppm (3H, d, J = 6.0, CH3); IR (CH2CI2) * 0 max: 3580 (weak, OH), 1770 (strong, C = 0 of fi> -lactam), 1700 (strong, C = 0 of lactone) and 1640 cm ”l (medium, olefin).

v

V

CD.YCM.3F - 45 - SY-1757

Claims (28)

1. H / - "- y Ilb where X represents a chloro, bromo, iodo or phenylseleno radical and R" represents a conventional radical protecting the hydroxyl function, characterized in that the intermediate of formula: OH IXH 1 Ν is converted "Υ Ha where X is as defined above by the corresponding intermediate in the formula from which the hydroxyl radical is protected by a conventional radical protecting the hydroxyl function. 1. Compound of formula: OR 'F X y / - »- y II where X represents a chloro, bromo, iodo or phenylseleno radical and R' represents a hydrogen atom or a conventional radical protecting the hydro-xyl function. 2. Compound according to claim 1, in the formula of which R ′ represents a bulky triorganosilyl radical protecting the hydroxyl function. 3. Compound according to claim 2, in the formula of which R 'represents a triisopropylsilyl, t-butyldimethylsilyl or t-butyldiphenyl-silyl radical. 4. Compound of formula: 0R ‘F x ü —V where X represents a bromo radical and R 'represents a hydrogen atom or a conventional radical protecting the hydroxyl function. 5. Compound according to claim 4 of formula: CD.YCM.4F - 46 - SY-1757 OH * V ψ / - "- y 6. A compound according to claim 4 of formula: OR "I · oJ — n — y where R" represents a conventional radical protecting the hydroxyl function. 7. A compound according to claim 6, in which the formula R "represents a bulky triorganosilyl radical protecting the hydroxyl function. 8. A compound according to claim 7, in which formula R ”represents a t-butyldime-thylsilyl, triisopropylsilyl or t-butyldiphenylsi-lyl radical. 9. Compound of formula: y N y III Λ where R ’represents a hydrogen atom or a conventional radical protecting the hydroxyl function. CD.YCM.4F - 47 - SY-1757 10. Compound according to claim 9 of - formula: J u-r Ilia 11. A compound according to claim 9 of formula: OR "I H H _L ^ SN ^ ° is irr γ 0 \ Illb where R" represents a conventional radical protecting the hydroxyl function. 12. Compound according to claim 11, in the formula of which R ″ represents a bulky triorganosilyl radical protecting the hydroxyl function. 13. A compound according to claim 12, in the formula of which R ″ represents a t-butyldime-thylsilyl, triisopropylsilyl or t-butyldiphenyl-silyl radical. 14. Process for the preparation of an intermediate of formula: C CD.YCM.4F - 48 - SY-1757 è OR "" IHH ί ΛΔ_> sn ^ ° p RT Γ O \ nib where R "represents a classical protective radical of the hydroxyl function, characterized in that it comprises the stages: (a) of reacting a 6,6-disubstituted arihydropenicillin of formula s y__ J— "> γ" V where X and Y each independently represent a chloro, bromo radical , iodo or phenylseleno with a reactant chosen between a Grignard reagent of formula R ^ MgX and an organolithic compound of formula RjLi, where Rj represents a lower alkyl or aryl radical and X is as defined above, in an inert organic solvent anhydrous and at a temperature of about 0 to -78 ° C, and then adding acetaldehyde to exclusively form the cis isomer of formula: CD.YCM.4F - 49 - SY-1757 * · 'OH | XH; AUfY 'J— · ly Ha where X is as defined above; (b) convert the intermediate Ha into the corresponding intermediate of formula : OR "IXH /" Ilb * · where R "represents a conventional radical protecting the hydroxyl function -r and X is as defined above, and (c) subjecting the intermediate Ilb to reduction in an inert solvent and to isolate the 5,6-trans isomer resulting from formula: OR "ï HH ΛΛ_> sp SET 0 \ Illb 'where R" is as defined above. 15.- Method according to claim 14, CD.YCM.4F - 50 - SY-1757 4- characterized in that in stage (b) the intermediate lia T is converted into the intermediate of formula: v î XH Ilb where R "represents a bulky triorganosilyl radical protecting the hydroxyl function. 16.- Process for the preparation of an intermediate of formula: OR 'Ju -Ιγ · III where R' represents a hydrogen atom or a conventional radical protecting the hydroxyl function, characterized in that it comprises the stages of: (a) reacting a 6,6-disubstituted anhydropenicillin of formula: bv— —yv CD.YCM.4F - 51 - SY-1757 ^ where X and Y each independently represent a chloro, bromo, iodo or phenylseleno radical, with a reactant ^ chosen between a Grignard reagent of formula R ^ MgX and an organolithic compound of formula RiLi, where Ri represents a lower alkyl or aryl radical and X is as defined above, in an anhydrous inert organic solvent and at a temperature of approximately 0 to -78 ° C., and then adding acetaldehyde to exclusively form the cis isomer of formula: OH VXH / Κτ- ^ 5γ ° Ha where X is as defined above; - (b) subjecting intermediate 11a to reduction in an inert solvent and isolating the 5,6- * trans isomer resulting from formula I "Y Ilia and, if desired, (c) convert the intermediate IIla to the corresponding intermediate of formula: Xi CD.YCM.4F - 52 - SY-1757 Y OR "IHH c. if T ° \ Illb where R ”represents a conventional radical protecting the hydroxyl function. 17, - Process for the preparation of a compound of formula: OH I "" / K,> sy ° R R | 0J - »- L lia r φ - where X represents a chloro, bromo, iodo or phenylsélénazo radical, characterized in that an intermediate of formula is reacted: J— ~ y V where X and Y each independently represent a chloro radical , bromo, iodo or phenylséléno, with a reactant N · - chosen between a Grignard reagent of formula R ^ MgX and an organolithic compound of formula RiLi, where Ri CD.YCM.4F - 53 - SY-1757 represents a lower alkyl radical or aryl and X * "* is as defined above, in an anhydrous 4-inert organic solvent, at a temperature of about 0 to -78 ° C., and then to add acetaldehyde to exclusively form the (8R ) -hydroxyethyl-cis isomer researched, of formula II. 18. Method according to claim 17, \ characterized in that the starting compound is Br Br ’fr’Y - -for / -> - * Y / --- 1V 19. The method of claim 17, characterized in that the starting compound is 6,6-dibromoanhydropenicillin. 20. The method of claim 17, 18 ^ or 19, characterized in that the Grignard ^ reagent used is methylmagnesium bromide. 21. The method of claim 17, 18 or 19, characterized in that the Grignard reagent used is methylmagnesium chloride. 22. Method according to claim 17, characterized in that the 6,6-dibromoanhy-dropenicillin is reacted in an inert organic solvent with approximately a molar equivalent of methylmagnesium chloride at a temperature of about -45 ° C to - 40 ° C, - then a molar excess of acetaldehyde is added. 23. The method of claim 17, characterized in that the 6,6-dibromoanhy-dropenicillin is reacted in an inert organic solvent with approximately v a molar equivalent of methylma- gnesium bromide at a temperature of approximately -20eC, then we _> CD.YCM.4F - 54 - SY-1757 adds a molar excess of acetaldehyde. 24.- Process for the preparation of a compound of W v formula ï OR " 25. The method of claim 24, characterized in that the intermediate lia 'is converted into an intermediate of formula: CD.YCM.4F - 55 - SY-1757 v ""' VXH o> - "- γ Ilb 1 where R "represents a bulky triorganosilyl radical protecting the hydroxyl function. 26. The method of claim 25, characterized in that the protective radical of the hydroxyl function is a triisopropylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl radical. 27. The method of claim 25, characterized in that the compound of formula is reacted: J ° HI Br A> sy ° J - »- \ in an inert organic solvent at a temperature ranging from about -40eC at room temperature with a bulky triorganosilylating agent in the presence of a base. 28. The process as claimed in claim 27, characterized in that the reaction is carried out with t-butyldimethylsilyl triflate, t-bu-k tyldiphenylsilyl triflate or triisopropylsilyl s triflate in a solvent chosen from methylene chloride , 4rx c tetrahydrofuran, chloroform, toluene and CD.YCM.4F - 56 - SY-1757 »f - diethyl ether and in the presence of an organic base. K - * * w J * CD.YCM.4F - 57 - SY-1757